Recent work suggests that asbestos and SV40 can act as co-carcinogens in the etiology of malignant[unreadable] mesothelioma (MM) and that AKT, a critical mediator of cell survival signals, is frequently activated in this[unreadable] disease. Human MMs often exhibit mutation of the NF2 tumor suppressor gene (TSG). Furthermore,[unreadable] homozygous deletion of the INK4a/ARF locus, which encodes the TSG products p16(INK4a) and p14(ARF),[unreadable] is frequently observed, although the relative contribution of p16(INK4a) versus p14(ARF) in MM[unreadable] pathogenesis has not been elucidated. Our hypothesis is that alterations of these three TSGs and[unreadable] expression of SV40 and AKT oncoproteins represent key disturbances in mesothelial cell physiology that[unreadable] collectively contribute to the development of MM. Understanding the molecular pathogenesis of MM and[unreadable] signaling pathways perturbed in this malignancy may elucidate invaluable molecular targets for[unreadable] therapeutic/preventive intervention, which is the broad, long-term objective of this project. The specific aims[unreadable] are: 1) Using in vitro and in vivo assays, we will determine whether restoration of NF2 expression can inhibit[unreadable] the growth and invasiveness of NF2-deficient MM cells. We will also conduct experiments to evaluate the[unreadable] therapeutic potential of adenovirus-mediated expression of NF2 and selective PAK inhibitors, as well as[unreadable] experiments to further elucidate merlin's function. 2) Using various murine knockout models, evaluate the[unreadable] relative contribution of Nf2, p19(Arf), and p16(lnk4a) inactivation to induction of MM by asbestos. Molecular[unreadable] genetic characterization of tumors derived from these mice will be conducted to establish the requirement[unreadable] for biallelic inactivation of the predisposing TSG and/or cooperation of oncogenes or other TSGs. We will[unreadable] compare susceptibility to asbestos-induced MM in p16(lnk4a)+/-, p14(Arf)+/- and doubly heterozygous[unreadable] Ink4a/Arf+/- mice in the same genetic background. In addition, determine if a SV40 Tag/tag mouse model is[unreadable] predisposed to MM spontaneously and/or following treatment with asbestos. 3) Further characterize the[unreadable] involvement of AKT in MM and determine whether pharmacologic inhibition of the AKT signaling pathway[unreadable] can repress MM cell growth and if combining an AKT pathway inhibitor with chemotherapeutic agents[unreadable] having a different mode of action results in increased efficacy. This Project will provide important insights[unreadable] regarding the involvement of key oncoproteins and TSG products in the pathogenesis of MM and will benefit[unreadable] from the availability of human and hamster MM samples through Project 1 and Cores B and C as well as[unreadable] from co-carcinogenesis and signaling work conducted in Project 2.